Treatment of type 2 diabetes mellitus to improve glycemic control in combination with other agents or as monotherapy.
Post-administration of saxagliptin, GLP-1 and GIP levels rise up to 2- to 3- fold. Because it is very selective of DPP-4 inhibition, there are fewer systemic side effects. Saxagliptin inhibits DPP-4 enzyme activity for a 24-hour period. It also decreased glucagon concentrations and increased glucose-dependent insulin secretion from pancreatic beta cells. The half maximal inhibitory concentration (IC50) is 0.5 nmol/L. Saxagliptin did not prolong the QTc interval to a clinically significant degree.
Mode of Action:
Saxagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor antidiabetic for the treatment of type 2 diabetes. DPP-4 inhibitors are a class of compounds that work by affecting the action of natural hormones in the body called incretins. Incretins decrease blood sugar by increasing consumption of sugar by the body, mainly through increasing insulin production in the pancreas, and by reducing production of sugar by the liver. [Bristol-Myers Squibb Press Release] DPP-4 is a membrane associated peptidase which is found in many tissues, lymphocytes and plasma. DPP-4 has two main mechanisms of action, an enzymatic function and another mechanism where DPP-4 binds adenosine deaminase, which conveys intracellular signals via dimerization when activated. Saxagliptin forms a reversible, histidine-assisted covalent bond between its nitrile group and the S630 hydroxyl oxygen on DPP-4. The inhibition of DPP-4 increases levels active of glucagon like peptide 1 (GLP-1), which inhibits glucagon production from pancreatic alpha cells and increases production of insulin from pancreatic beta cells.
The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). 50% of the absorbed dose will undergo hepatic metabolism. The major metabolite of saxagliptin, 5-hydroxy saxagliptin, is also a DPP4 inhibitor, which is one-half as potent as saxagliptin.
Adverse reactions reported in ≥5% of patients treated with saxagliptin and more commonly than in patients treated with placebo are: upper respiratory tract infection, urinary tract infection, and headache.
Rosenstock J, Sankoh S, List JF: Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes. Diabetes Obes Metab. 2008 May;10(5):376-86. Epub 2008 Mar 18. PubmedMetzler WJ, Yanchunas J, Weigelt C, Kish K, Klei HE, Xie D, Zhang Y, Corbett M, Tamura JK, He B, Hamann LG, Kirby MS, Marcinkeviciene J: Involvement of DPP-IV catalytic residues in enzyme-saxagliptin complex formation. Protein Sci. 2008 Feb;17(2):240-50. PubmedCrepaldi G, Carruba M, Comaschi M, Del Prato S, Frajese G, Paolisso G: Dipeptidyl peptidase 4 (DPP-4) inhibitors and their role in Type 2 diabetes management. J Endocrinol Invest. 2007 Jul-Aug;30(7):610-4. PubmedBarnett A: DPP-4 inhibitors and their potential role in the management of type 2 diabetes. Int J Clin Pract. 2006 Nov;60(11):1454-70. Pubmed# Kulasa K, Edelman S: Saxagliptin: the evidence for its place in the treatment of type 2 diabetes mellitus. Core Evid. 2010 Oct 21;5:23-37. Pubmed
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